Our laboratory studies the role of a transcriptional represser called B Lymphocyte Induced Maturation[unreadable] Protein -1 (Blimp-1). Blimp-1 controls critical cascades of gene regulation in B and T lymphocytes and is[unreadable] required for terminal differentiation of B cells and for development and homeostasis of T cells. Blimp-1 is[unreadable] also expressed in epithelial cells. We have recently created mice with a keratinocyte-specific deletion of[unreadable] Blimp-1 using keratin-14 Cre mice. These mice have defects in the granular layer/stratum corneum[unreadable] transition and formation of the stratum corneum, defects in sebocyte differentiation and sebum release and[unreadable] delayed hair cycle. Our long-range goal is to take advantage of this requirement for Blimp-1 in epidermis to[unreadable] learn more about molecular mechanisms of gene regulation that control differentiation of interfollicular[unreadable] keratinocytes, sebocytes and inner root sheath cells of the hair follicle.[unreadable] In this proposal, we will focus on the defect in the granular layer/stratum corneum transition of IFE[unreadable] keratinocytes in mice having a keratinocyte-specific conditional knock-out of Blimp-1 (CKO). We will[unreadable] perform biochemical, immunofluorescence and electron microscopic studies to thoroughly characterize the[unreadable] developmental defect. Then we will perform global gene expression studies on cells from control and CKO[unreadable] mice to identify and subsequently verify gene expression programs in granular layer cells that are regulated[unreadable] by Blimp-1. This work will provide the basis for subseuent studies to identify, both mechanistically and[unreadable] functionally, critical regulators of the granular layer/stratum corneum transition. Such information will aid in[unreadable] understanding diseases affecting the formation of normal stratum corneus and may provide targets for the[unreadable] development of drugs to modify misregulated differentiation.[unreadable] Dr. Calame qualifies as Category #2 in the Guidelines as an Established Investigator with no previous work[unreadable] in skin diseases. This P&F study will use Cores A and B.